Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and Braf^V600E-Induced Tumorigenesis.

ABSTRACT: We addressed the precursor role of aging-like spontaneous promoter DNA hypermethylation in initiating tumorigenesis. Using mouse colon-derived organoids, we show that promoter hypermethylation spontaneously arises in cells mimicking the human aging-like phenotype. The silenced genes activate the Wnt pathway, causing a stem-like state and differentiation defects. These changes render aged organoids profoundly more sensitive than young ones to transformation by Braf^V600E, producing the typical human proximal BRAF^V600E-driven colon adenocarcinomas characterized by extensive, abnormal gene-promoter CpG-island methylation, or the methylator phenotype (CIMP). Conversely, CRISPR-mediated simultaneous inactivation of a panel of the silenced genes markedly sensitizes to Braf

SUBMITTER: Tao Y 

PROVIDER: S-EPMC6636642 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature